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2016 Grants - Hu

The Role of Hyperphosphorylation in the Spread of Tau Pathology

Wen Hu, Ph.D.
New York State Institute for Basic Research in Developmental Disabilities
Staten Island, New York

2016 New Investigator Research Grant

How does a specific modification of the tau protein promote its accumulation and spread through the brain in Alzheimer’s disease?

Background
Tau protein, which normally helps nerve cells maintain their proper shape and transport nutrients, becomes modified during Alzheimer’s disease. One type of modification is the addition of a phosphate molecule to specific parts of the tau protein. In Alzheimer’s disease, tau molecules become excessively phosphorylated and lose their ability to carry out normal activities. Such “hyperphosphorylated” tau also tends to change shape leading to its abnormal accumulation as “tangles” and spread throughout the brain.

In their initial studies, Wen Hu, Ph.D., and colleagues injected several types of abnormal tau into the brains of mice engineered to develop an Alzheimer’s-like condition. They found that only hyperphosphorylated tau could spread and clump together in harmful tangles. This finding suggests that hyperphosphorylation of tau may promote its toxic effects on nerve cells. However, the precise mechanisms by which hyperphosphorylation leads to the abnormal accumulation and spread of tau remain unclear.

Research Plan
For their research grant, Dr. Hu and colleagues plan to determine more precisely how abnormal phosphorylation takes place in tau protein. They will identify the specific sites on the tau molecule where this process occurs, as well as the level of hyperphosphorylation required to produce its abnormal shape and accumulation. This work will involve genetically engineering tau molecules that can be phosphorylated only at certain sites, and then determining whether the molecules can become hyperphosphorylated and develop neurofibrillary tangles. The researchers will also inject different types of hyperphosphorylated tau into the brains of mice and study which types are most likely to form tangles and cause nerve cell damage.

Impact
The results of Dr. Hu’s study could shed new light on how certain modifications of the tau protein may promote the formation of tangles and disease-related brain changes. This work could lead to the development of novel therapies that target and block these mechanisms to help prevent, slow or halt Alzheimer’s disease.